Process for the preparation of 4-hydroxystilbene and its derivatives



Guido Cavallini and n... ammal... nar

asslgnors to'Maggioni' d; S. p. A., Milan, Italy No Drawing. mutants May.17 195s. 1

i senn soans 2 "Claims. crate-T510 \Aprocess for preparing4-hydroxystilbene is described cedure described, when'performed on alaboratory scale,

has given very low yields namely, of some 10% of theory. l It is anobject of the present invention to provide a method for preparing4-hydroxystilbene with yields much greater than those obtained with themethod mentio ned above.

It is another object of the present invention, to provide methods forthe preparation of derivatives' of 4-hydroxy- .stilbene, particularly,4-hydroxy-4 chloro-stilbene, 4-

hydroxy-4-nitro-stilbene hene, which also produce relatively high yieldsof such 1" derivatives. a

and 4-hydroxy-4'-amino-stil- It has been surprisingly ascertained that,by adding piperidine to phenylacetic acid,there is a remarkable heatbuildupzand this phenomenon indicates the formation of a piperidine saltof thephenylaceti'c acid. Following the addition of jpiperidine tophenylacetic jj] acid, p-hydroxybenzaldehydefis introduced, and, the re-J action mixture is heatedatf atemperature of 100, C. I "and under avacuum (absolute pressure), of 16 mun jjfor 3. hours. Subsequently theinternal temperature is raised, still under the indicatedreducedpressure, up to 150 C.: and a product is obtained which has amelting It has also been unexpectedly. ascertained that, when theoperations set forth above are performed without t employing vacuum, orwhen the operationsare continued for different periods of time at steadytemperatures within the range 100 C. to A 180 -C., the yields decreaseto i 10% and the productobtainedhas amelting point ranging from 153 C.to 170 C. The purity of this product, furthermoreis notsatisfactory, asshown bythe wide -melting range, and consequently the product has to befurther purified, so that the actual yield is even lower Referring tothe foregoing, the basic' steps of the method embodying the inventionare the following:

(1) Introduction, in a reaction vessel, of piperidine and phenylaceticacid, at a temperature of not higher than 100 C., to form the piperidinesalt of the phenylacetic acid.

(2) Introduction of p-hydroxybenzaldehyde and subsequent evacuation ofthe reaction vessel while maintaining the temperature at a value rangingfrom 90 C. to 100 C. for a predetermined time, for instance 3 hours. Inthis step condensation takes place between p-hydroxy bcnzaldehyde andphenylacetic acid, and the elimination of the water which is a comequence of this reaction, is facilitated by the application of vacuum.

(3) The temperature is raised to 150 C. while vacu- U i t te Patent byHewitt in Chem. Soc. J. 101 (1912 6o4 s but the v yields obtained arenot reported, land, in fact, the prov material is p-chlorophenylaceticacid.

ice

2 um is still applied for a predetermined time, for intsance 3 hours, sothat the elimination of CO is speeded up and the reaction is thuscompletedqin the least possible time.

By adopting the above described steps, a mass is 0b tained from which,when it is dissolved in an alkaline solution and subsequentlyneutralized, for intsance with CO 4-hydroxystilbene, or a derivativethereof, is precipitated in crystallized form.

The 4-hydroxystilbene derivatives, substituted in 4 position, aresimilarly prepared, but the phenylacetic acid derivative then selectedas a startingmaterial is the one which contains, in the para position,the group which it is desired to introduce. Thus, for example, if4-hydroxy-4-nitrostilbene is to be produced, the starting material isp-nitro-phenylacetic acid, whereas, if" 4- hydroxy-4'-chloro-stilbene isto be produced, the starting The following specific examples willillustrate fthe -method embodying this invention:

EXAMPLE I 4-hyd r0xystilbe ne C 0, OH

l pip rl In a flask having three necks fitted with a cock-funnel,stirring means and thermometer, 40.8 grams of phenylacetic acid areintroduced and 25.6 grams of piperidine are then added drop-by-dropwhile cooling flask in an oil bath in order to avoid an increase. of theinternal temperature above 100 C. After the introduction of thepiperidine has been completed, the stirring is continued for anadditional 10 minutes until the temperature falls to 50 C. 36.6 grams ofp-hydroxy-benzaldehyde are now introduced. I

The cock-funnel is replaced by a capillary tube, while the thermometeris replaced by a lateral tube connected to a reflux refrigerator and toa collecting flask fitted with an inlet tube. The whole system isindirectly heated at 100 C. and the flask is kept evacuated, while theliquid is stirred, for 3 hours.

After such 3 hour period the external temperature is raised to C. for anadditional 3 hours. A dark paste is formed in the flask and istransferred, while still hot, to a mortar. When cool, this mass sets andcan be crushed. The product obtained is dissolved in 200 grams of aboiling 30% sodium hydroxide solution. The solution now obtained must bedefinitely alkaline when tested with phenolphthalein.

The solution is left to stand overnight at room temperature in ordertoobtain a slow crystallization forming crystals of a size sutficientfor centrifugation. Then the solution is centrifuged and the sodium saltof 4-hydroxystilbene is dissolved in 3 litres of cold water. Thissolution is treated with 1 g. of animal charcoal and filtered.

A stream of carbon dioxide is bubbled through the filtrate until thealkaline reaction (indicator: phenolphthalein) disappears. A slightlyyellow precipitate is obtained, which is centrifuged. The product isdried in an oven under vacuum at 50 C. Approximately 50 grams of4-hydroxystilbene are obtained, which yield corresponds to 86% of thetheoretical amount. The melting point is 184 C. to 186 C. The producthas a satisfactory purity which is not improved by crystallizing itagain from alcohol.

3 EXAMPLE II 4-hydroxy-4'-chlam-stilbene Reaction diagram:

COOH

CIO-CH1 orro-O-on l piperidine) and then crushed, and thereafter thereis extracted from said paste, through crystallization from glacialacetic acid,

the 4- hydroxy-4'chlorostilbene. 57.3 grams of4-hydroxy-4'-chlorostilbene are obtained, which corresponds to 83% ofthe theoretical yield.

The product has a melting point of 182 C.

NCO-(7H2 crroO-on l piperidine) In a flask having three necks fittedwith a cock-funnel, stirring means and thermometer, 54.3 grams ofp-nitrophenylacetic acid are introduced and 25.6 grams of piperidine areadded drop-by drop while the flask is cooled in an oil-bath in order toavoid an increase in the internal temperature above 100 C.

From this point onwards the procedure of Example I i is followed, stepby step, until a dark paste is obtained In a flask having three necksfitted with a cock-funnel, stirring means and thermometer, 57.9 grams ofp-acetylaminophenylacetic acid are introduced and 25.6 grams ofpiperidine are added drop-by-drop while cooling the flask in order toavoid an increase of the internal temperature above 100 C. From thispoint onwards the procedure of Example I is followed, step by step,until a dark paste is obtained inthe flask which is transferred, whilestill hot, to a mortar, where it is allowed to set and crushed. Theproduct thus obtained is dissolved in about 200 grams of a boilingsolution of sodium hydroxide. The solution now obtained must give adefinitely alkaline reaction with phenolphthalein. Astream of CO isbubbled through the last mentioned solution until the alkaline reactionto phenolphthalein disappears. A light-yellow precipitate is obtained,which is centrifuged and dried in an oven, under vacuum, at 50 C.

50 grams of 4-hydroxy-4-amino stilbene are obtained, which correspondsto 80% of the theoretical yield. The melting point of this product is270 C.

The 4-hydroxystilbenes and the derivatives thereof which are prepared inaccordance with this invention are useful intermediates in thepreparation of synthetic hormones such as alkylaminopropyl derivativesdescribed in copending patent application Serial No. 509,115, filed May17, 1955, by the present applicants and now abandoned.

What we claim is: 1. A process for the preparation ofmernbers of thegroup consisting of 4-,hydroxystilbene, 4-hydroxy-4'-ehlorostilbene,4-hydroxy- '-.nitro-s tilbene and 4-hydroxy-4'- aminostilbene whichcomprises reacting piperidine and a member of'the group consisting ofphenylacetic acid and in the flask which is transferred, while stillhot, to amortar, where it is allowed to set and then crushed. Then thereis extracted from said paste, through crystallization from acetic acid,4-hydroxy-4'-nitro-stilbene.

54 grams of 4-hydroxy-4-nitro-stilbene are obtained,

, which correspond to of the theoretical yield.

l -crn 0300-011 1 piperidine) the derivatives thereof containing in the4'-position a monovalent group which is selected from the classconsisting of chloro, nitroand amino groups, in substantiallyequi-molecular proportions and controlling the temperature of theresulting exothermic reaction so that the temperature during saidreaction will not exceed C., then adding parahydroxybenzaldehyde in asubstantially equi-molecular proportion to the phenylacetic acid "andheating the reaction mixture at an absolute pressure of about 16 mm. ofmercury and a temperatnre of 100 to C. until the reaction ceases.

2. The process of claim 1 in which the reaction product is dissolved instrong hot alkali metal hydroxide solution filtered and decolorized andthen neutralized with carbon dioxide until a precipitate is obtained,which is recovered.

References Cited in the file of this patent Hewitt et al.: Chem. Soc.Journal, vol. 101 (1912), pp. 604-5.

J. Prakt Chem., vol. 152, pp. 237-66 (1937). I

Brownlee et al.: Biochemical Journal, vol. 37 (1943), pp. 572-77. r

Chemical Abstracts, vol. 48, 1954, page 2670b...

Journal of the Chemical Soc. London, vol. 101,.p. 606 (Hewitt et al.).

Journal of the Chemical Soc. London, vol. 123, p. 2056 '(Cullinare).

1. A PROCESS FOR THE PREPARATION OF MEMBERS OF THE GROUP CONSISTING OF4-HYDROXYSTILBENE, 4-HYDROXY-4''ROSTILBENE, 4-HYDROXY-4''-NITRO-STILBENEAND 4-HYDROXY-4''AMINOSTILBENE WHICH COMPRISES REACTING PIPERIDINE AND AMEMBER OF THE GROUP CONSISTING OF PHENYLACETIC ACID AND THE DERIVATIVESTHEREOF CONTAINING IN THE 4''-POSITION A MONOVALENT GROUP WHICH ISSELECTED FROM THE CLASS CONSISTING OF CHLORO, NITRO AND AMINO GROUPS, INSUBSTANTIALLY EQUI-MOLECULAR PROPORTIONS AND CONTROLLING THE TEMPERATUREOF THE RESULTING EXOTHERMIC REACTION SO THAT THE TEMPERATURE DURING SAIDREACTION WILL NOT EXCEED 100*C., THEN ADDING PARAHYDROXYBENZALDEHYDE INA SUBSTANTIALLY EQUI-MOLECULAR PROPORTION TO THE PHENYLACETIC ACID ANDHEATING THE REACTION MIXTURE AT AN ABSOLUTE PRESSURE OF ABOUT 16 MM. OFMERCURY AND A TEMPERATURE OF 100 TO 150*C. UNTIL THE REACTION CEASES.